Human papilloma viruses (HPVs) encompass the most common "carcinogenic" viruses. While an oncogenic role of HPVs has been established for anogenital cancers, an etiologic relationship for keratinocyte cancers (i.e., squamous cell carcinoma (SCC) of the skin) is unclear. Part of the uncertainty stems from the lack of large, population-based studies. About 90% of skin cancers from immunocompromised individuals and an estimated 30% to 50% of those from immunocompetent individuals contain cutaneous or phylogenic group B HPV DNA. Emerging data also suggest that the presence of antibodies to cutaneous types of HPVs may be associated with risk of keratinocyte cancers, in particular SCC. Recent advancements in analytic techniques make it possible to efficiently detect a wide range of cutaneous HPV types both serologically and in tumor samples. We propose to evaluate the etiologic role of HPV in SCC using accrued biologic materials and epidemiologic data from a completed population-based study of keratinocyte cancers in New Hampshire. We propose to test for the presence of HPV antibody in blood samples (671 SCC and 812 controls) and for HPV DNA in tumor tissue samples (416 SCC cases). Serologic testing will target antibodies to the capsid and early proteins of at least 16 cutaneous HPV types including types 5, 8, 9, 15,17, 20, 23, 24, 36, 38, 49, 75, 76, 92, 93, 96 along with non-cutaneous types as specificity controls. We will further test for the presence of HPV DNA in tumor tissue and examine constitutional genetic variation in \beXRCC1, EVER1, EVER2 and p53 genes as potential modifiers of SCC susceptibility related to HPV infection. We will explore the hypothesis that use of immunosuppressive drugs (i.e., glucocorticoids) or exposure to other potential skin cancer carcinogens (i.e., excess ultraviolet light or cigarette smoking) may enhance risk of HPV-related SCCs. Our study provides a unique opportunity to gain a more complete understanding of the role of cutaneous HPV types in the etiology of keratinocyte malignanices, which, in turn, may guide the design of novel treatment and preventive strategies. Relevance: Skin cancers (keratinocyte tumors) are by far the most commonly occurring cancers in humans, with a growing health and economic burden in our population. Infection with human papilloma viruses, which play a key role in other cancers (e.g., cancer of the cervix), may increase risk for skin cancer, and therefore may offer previously unrecognized treatment and preventive strategies. Using available data and biologic samples from a large epidemiologic study, and applying recent advances in HPV detection, we will conduct a comprehensive investigation of the role of human papilloma viruses in skin cancer occurrence.